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Details for Patent: 5,314,679

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Details for Patent: 5,314,679

Title: Vascular magnetic resonance imaging agent comprising nanoparticles
Abstract:The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.
Inventor(s): Lewis; Jerome M. (Newton, MA), Menz; Edward T. (Quincy, MA), Kenny; Francis E. (Watertown, MA), Groman; Ernest V. (Brookline, MA), Josephson; Lee (Arlington, MA)
Assignee: Advanced Magnetics Inc. (Cambridge, MA)
Filing Date:Dec 22, 1992
Application Number:07/995,111
Claims:1. A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent:

i) comprises a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return by proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels; and (b) are associated with a protein; and

ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.

2. A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent:

(i) comprises a population of biodegradable superparamagnetic metal oxide, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and

(ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.

3. A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent:

(i) comprises a population of biodegradable metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with hydroxethyl starch; and

(ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.

4. The magnetic resonance imaging contrast agent of claim 1 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.

5. The magnetic resonance imaging contrast agent of claim 2 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.

6. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.

7. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said metal oxide is selected from the group consisting of chromium, cobalt, copper, manganese, molybdenum, nickel and tungsten oxides.

8. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said metal oxide is iron oxide.

9. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 which comprises a population of particles wherein the mean diameter of an individual particle is about 180 .ANG. or less, as measured by light scattering.

10. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said blood half-life is at least about 49 minutes in rat at a dose of 2 mg per metal per kg rat.

11. The magnetic resonance imaging contrast agent of claim 10 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.

12. The magnetic resonance imaging contrast agent of claim 10 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.

13. The magnetic resonance imaging contrast agent of claim 10 in which said particles comprises aggregates of individual biodegradable superparamagnetic metal oxide crystals.

14. The magnetic resonance imaging contrast agent of claim 10 which comprises a population of particles wherein the mean diameter of an individual particle is about 150 .ANG. or less, as measured by light scattering.

15. The magnetic resonance imaging contrast agent of claim 14 in which said polypeptides is selected from the group consisting of polyglutamate and polylysine.

16. The magnetic resonance imaging contrast agent of claim 14 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.

17. The magnetic resonance contrast imaging contrast agent of claim 14 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin, and heparin.

18. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species has a molecular weight of about 1 to about 250 kd.

19. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species and said metal are present at a weight ratio of about 0.1 to about 10.

20. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to 0.2.

21. The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said contrast agent is capable of providing a contrast effect selected from the group consisting of a darkening effect, a brightening effect, and a combined darkening and brightening effect.

22. A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises:

(a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent;

(i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a protein; and

(ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat; and

(b) recording such MR image of the vascular compartment.

23. A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises:

(a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent

(i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and

(ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and

(b) recording such MR image of the vascular compartment.

24. A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises:

(a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent

(i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a hydroxyethyl starch; and

(ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and

(b) recording such MR image of the vascular compartment.

25. The method of claim 22 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.

26. The method of claim 21 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.

27. The method of claim 22, 23 or 24 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.

28. The method of claim 22, 23 or 24 in which said metal oxide is selected from the group consisting of chromium, cobalt, copper, manganese, molybdenum, nickel and tungsten oxides.

29. The method of claim 22, 23 or 24 in which said metal oxide is iron oxide.

30. The method of claim 22, 23 or 24 which comprises a population of particles wherein the mean diameter of an individual particle is about 180 .ANG. or less, as measured by light scattering.

31. The method of claim 22, 23 or 24 in which said blood half-life is at least about 49 minutes in rat at a dose of 2 mg per metal per kg rat.

32. The method of claim 22, 23 or 24 in which comprises a population of particles wherein the mean diameter of an individual particle is about 150 .ANG. or less, as measured by light scattering.

33. The method of claim 22, 23 or 24 in which said macromolecular species has a molecular weight of about 1 to 250 kd.

34. The method of claim 22, 23 or 24 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to about 10.

35. The method of claim 22, 23 or 24 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to about 0.2.

36. The method of claim 22, 23 or 24 in which said contrast agent is capable of providing a contrast effect selected from the group consisting of a darkening effect, a brightening effect, and a combined darkening and brightening effect.

37. The method of claim 31 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.

38. The method of claim 31 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.

39. The method of claim 31 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.

40. The method of claim 32 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.

41. The method of claim 32 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.

42. The method of claim 32 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
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